Peter J. Mazzone

Screening for Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths. METHODS A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer. RESULTS Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature. CONCLUSIONS Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale.

Analysis of Volatile Organic Compounds in the Exhaled Breath for the Diagnosis of Lung Cancer

Volatile organic compounds are able to be detected in the exhaled breath by a variety of sensing techniques. These volatiles may be produced by cellular metabolic processes, or inhaled/absorbed from exogenous sources. Lung cancer cells may produce and process these compounds different than normal cells. The differences may be detectable in the breath. The following manuscript will review the evidence supporting the premise that a unique chemical signature can be detected in the breath of patients with lung cancer, discuss the results of studies using mass spectrometry and nonspecific chemical sensing techniques to detect the unique lung cancer signature, and speculate on the advancements that must occur to develop a breath test accurate enough to be clinically useful.

Exhaled breath analysis with a colorimetric sensor array for the identification and characterization of lung cancer.

Introduction: The pattern of exhaled breath volatile organic compounds represents a metabolic biosignature with the potential to identify and characterize lung cancer. Breath biosignature-based classification of homogeneous subgroups of lung cancer may be more accurate than a global breath signature. Combining breath biosignatures with clinical risk factors may improve the accuracy of the signature. Objectives: To develop an exhaled breath biosignature of lung cancer using a colorimetric sensor array and to determine the accuracy of breath biosignatures of lung cancer characteristics with and without the inclusion of clinical risk factors. Methods: The exhaled breath of 229 study subjects, 92 with lung cancer and 137 controls, was drawn across a colorimetric sensor array. Logistic prediction models were developed and statistically validated based on the color changes of the sensor. Age, sex, smoking history, and chronic obstructive pulmonary disease were incorporated in the prediction models. Results: The validated prediction model of the combined breath and clinical biosignature was moderately accurate at distinguishing lung cancer from control subjects (C-statistic 0.811). The accuracy improved when the model focused on only one histology (C-statistic 0.825–0.890). Individuals with different histologies could be accurately distinguished from one another (C-statistic 0.864 for adenocarcinoma versus squamous cell carcinoma). Moderate accuracies were noted for validated breath biosignatures of stage and survival (C-statistic 0.785 and 0.693, respectively). Conclusions: A colorimetric sensor array is capable of identifying exhaled breath biosignatures of lung cancer. The accuracy of breath biosignatures can be optimized by evaluating specific histologies and incorporating clinical risk factors.

American College of Chest Physicians and Society of Thoracic Surgeons Consensus Statement for Evaluation and Management for High-Risk Patients with Stage I Non-small Cell Lung Cancer

BACKGROUND The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity. METHODS A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved. RESULTS Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking. CONCLUSIONS Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date.

Lung cancer biomarkers in exhaled breath

Lung cancer is the leading cause of cancer-related mortality worldwide. Methods for early detection of lung cancer, such as computerized tomography scanning technology, often discover a large number of small lung nodules, posing a new problem to radiologists and chest physicians. The vast majority of these nodules will be benign, but there is currently no easy way to determine which nodules represent very early lung cancer. Adjuvant testing with PET imaging and nonsurgical biopsies has a low yield for these small indeterminate nodules, carries potential morbidity and is costly. Indeed, purely morphological criteria seem to be insufficient for distinguishing lung cancer from benign nodules at early stages with sufficient confidence, therefore false positives undergoing surgical resection frequently occur. A molecular approach to the diagnosis of lung cancer through the analysis of exhaled breath could greatly improve the specificity of imaging procedures. A biomarker-driven approach to signs or symptoms possibly due to lung cancer would represent a complementary tool aimed at ruling out (with known error probability) rather than diagnosing lung cancer. Volatile and nonvolatile components of the breath are being studied as biomarkers of lung cancer. Breath testing is noninvasive and potentially inexpensive. There is promise that an accurate lung cancer breath biomarker, capable of being applied clinically, will be developed in the near future. In this article, we summarize some of the rationale for breath biomarker development, review the published literature in this field and provide thoughts regarding future directions.

Bronchoscopy and needle biopsy techniques for diagnosis and staging of lung cancer.

Lung cancer is the leading cause of cancer deaths in the United States. The individual therapeutic approach and prognosis depends on accurate diagnosis and staging. Flexible bronchoscopy (FB) and transthoracic needle biopsy (TNB) are the most widely used techniques for this purpose. This article provides a critical overview of indications, diagnostic yield, and limitations of bronchoscopy and TNB in the diagnosis of lung cancer.

A Comparison of Two Stereotactic Body Radiation Fractionation Schedules for Medically Inoperable Stage I Non-small Cell Lung Cancer: The Cleveland Clinic Experience

Purpose: To assess the impact of fractionation upon tumor control and toxicity in medically inoperable early stage lung cancer patients treated with stereotactic body radiotherapy. Methods: We reviewed 94 consecutive stereotactic body radiotherapy treatments (86 patients) with medically inoperable stage I non-small cell lung cancer receiving either 50 Gy in five fractions (n = 56) or 60 Gy in three fractions (n = 38) from October 2003 to August 2007. Institutional practice was 10 Gy × 5 before March 1, 2006, when it changed to 20 Gy × 3 to conform to Radiation Therapy Oncology Group 0236 unless otherwise dictated clinically. Results: Median age was 73 years and median Karnofsky performance status 80. A total of 69 lesions were T1, 24 were T2 lung cancer. Median follow-up was 15.3 months. For the 50- and 60-Gy cohorts at 1 year, local control was 97.3% versus 100%, nodal failure 7.3% versus 3.4%, distant metastasis rate 21.8% versus 29.5%, and overall survival 83.1% versus 76.9% (p = 0.68, 0.54, 0.56, and 0.54, respectively). There was no difference in overall survival for patients with histologic (n = 61) compared with radiographic (n = 33) diagnosis. There was no impact of fractionation in the subset of T2 tumors. We observed two cases (2.2%) of clinical grade 2 pneumonitis. Mild late chest wall toxicity (grade 1 or 2) was seen in nine patients (10%) at a median of 8.4 months after treatment and was more common in the 60-Gy group (7 of 38 [18%] versus 2 of 56 [4%], p = 0.028). Conclusions: Local control, overall survival, nodal failure, and distant failure were not affected by fractionation. Chest wall toxicity was more common with 60-Gy group.

Comprehensive Analysis of Pulmonary Function Test (PFT) Changes After Stereotactic Body Radiotherapy (SBRT) for Stage I Lung Cancer in Medically Inoperable Patients

Background: To assess for variables predicting pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for medically inoperable stage I lung cancer. Methods: We reviewed 92 consecutive patients undergoing SBRT for stage I lung cancer between February 2004 and August 2007. A total of 102 lesions were treated using prescriptions of 20 Gy × 3 (n = 40), 10 Gy × 5 (n = 56), and 5 Gy × 10 (n = 6). Institutional practice was 10 Gy × 5 before March 1, 2006 before changing to 20 Gy × 3 to conform to RTOG 0236 unless otherwise dictated clinically. Results: Median pretreatment forced expiratory volume at 1 second (FEV1) was 1.21 liter (50% of predicted) and median diffusion capacity to carbon monoxide (DLCO) was 56.5. There was no significant overall change in PFTs after SBRT. Individual patients experienced both substantial improvements and declines (10% declined at least 14% predicted FEV1% and 19% predicted DLCO). The mean change in FEV1 was −0.05 liter (range, −0.98 to +1.29 liter; p = 0.22) representing −1.88% predicted baseline FEV1 (range, −33 to + 43%; p = 0.62). DLCO declined 2.59% of predicted (range, −37 to +33%; p = 0.27). Conformality index, V5 and V10 were associated with individual patient changes in FEV1% (p = 0.033, p = 0.0036, p = 0.025, respectively), however, correlations were small and overall treatment dose did not predict for changes (p = 0.95). There was no significant difference in FEV1 (p = 0.55) or FEV1% (p = 0.37) changes for central versus peripheral locations. No factors predicted for individual changes in DLCO. Patients with FEV1% below the median of the study population had significantly longer overall survival (p = 0.0065). Although patients dying of cardiac disease died earlier than those dying of other causes, FEV1% below median was not associated with a lower risk of dying of cardiac disease or with lower Charlson comorbidity index. Conclusions: (1) SBRT was well tolerated and PFT changes were minimal. (2) Central lesions were safely treated with 50 Gy.

The effect of metformin and thiazolidinedione use on lung cancer in diabetics

BackgroundMetformin and the thiazolidinediones (TZDs) may have a protective effect against the development of lung cancer.MethodsPatients with diabetes mellitus (DM) were identified from the electronic medical records of the Cleveland Clinic. Diabetics with lung cancer were identified then verified by direct review of their records. Control subjects were matched with cancer subjects 1:1 by date of birth, sex, and smoking history. The frequency and duration of diabetic medication use was compared between the groups. The cancer characteristics were compared between those with lung cancer who had and had not been using metformin and/or a TZD.Results93,939 patients were identified as having DM. 522 lung cancers in 507 patients were confirmed. The matched control group was more likely to have used metformin and/or a TZD (61.0% vs. 41.2%, p < 0.001 for any use; 55.5% vs. 24.6%, p < 0.001 for >24 months vs. 0–12 months). In the group with lung cancer, those who had used metformin alone had a different histology distribution than those who received neither metformin nor a TZD, were more likely to present with metastatic disease (40.8% vs. 28.2%, p = 0.013), and had a shorter survival from the time of diagnosis (HR 1.47, p < 0.005).ConclusionsThe use of metformin and/or the TZDs is associated with a lower likelihood of developing lung cancer in diabetic patients. Diabetics who develop lung cancer while receiving metformin may have a more aggressive cancer phenotype.

Components Necessary for High-Quality Lung Cancer Screening: American College of Chest Physicians and American Thoracic Society Policy Statement

Lung cancer screening with a low-dose chest CT scan can result in more benefit than harm when performed in settings committed to developing and maintaining high-quality programs. This project aimed to identify the components of screening that should be a part of all lung cancer screening programs. To do so, committees with expertise in lung cancer screening were assembled by the Thoracic Oncology Network of the American College of Chest Physicians (CHEST) and the Thoracic Oncology Assembly of the American Thoracic Society (ATS). Lung cancer program components were derived from evidence-based reviews of lung cancer screening and supplemented by expert opinion. This statement was developed and modified based on iterative feedback of the committees. Nine essential components of a lung cancer screening program were identified. Within these components 21 Policy Statements were developed and translated into criteria that could be used to assess the qualification of a program as a screening facility. Two additional Policy Statements related to the need for multisociety governance of lung cancer screening were developed. High-quality lung cancer screening programs can be developed within the presented framework of nine essential program components outlined by our committees. The statement was developed, reviewed, and formally approved by the leadership of CHEST and the ATS. It was subsequently endorsed by the American Association of Throacic Surgery, American Cancer Society, and the American Society of Preventive Oncology.